Mechanochemical solid state synthesis of copper(I)/NHC complexes with K3PO4

A protocol for the mechanochemical synthesis of copper(I)/N-heterocyclic carbene complexes using cheap and readily available K3PO4 as base has been developed. This method employing a ball mill is amenable to typical simple copper(I)/NHC complexes but also to a sophisticated copper(I)/N-heterocyclic carbene complex bearing a guanidine moiety. In this way, the present approach circumvents commonly employed silver(I) complexes which are associated with significant and undesired waste formation and the excessive use of solvents. The resulting bifunctional catalyst has been shown to be active in a variety of reduction/hydrogenation transformations employing dihydrogen as terminal reducing agent.


General information
Liquid state reactions were carried out in flame dried glassware under a nitrogen atmosphere using standard Schlenk techniques. Glassware and stir bars contaminated with transition metals were treated with aqua regia (conc. HCl/conc. HNO3 3:1) prior to cleaning. For cleaning, glassware and stir bars were kept in an isoPrOH/KOH bath overnight, rinsed with H2O, kept in a citric acid/H2O bath overnight and finally rinsed with deionized H2O and dried at 120 °C.
Solutions and reagents were added with nitrogen-flushed disposable syringes/needles. Solvents were added using glass syringes and stainless-steel needles (stored at 120 °C).
Analytical thin layer chromatography (TLC) was performed on silica gel 60 G/UV254 aluminium sheets (Macherey-Nagel). Ball-milling experiments were carried out using a Fritsch Pulverisette 7 classic line planetary ball mill. NMR spectra were recorded on AV400, AV500 or AV700 instruments (Bruker) at the Institut für Chemie of Technische Universität Berlin.
Chemical shifts are reported in parts per million (ppm) and are referenced to the residual solvent resonance as the internal standard according to the standard literature.

Solvents
THF and 1,4-dioxane were dried over sodium/benzophenone and distilled under N2 atmosphere prior to use. Et3N, CH2Cl2 and MeOH were dried over CaH2 and distilled under N2 atmosphere prior to use. Acetone and EtOH were distilled under reduced pressure prior to use.
Solvents (technical grade) for extraction/chromatography (n-pentane, cyclohexane, CH2Cl2, tert-butyl methyl ether, EtOAc) were distilled under reduced pressure prior to use. Liquid substrates for hydrogenation reactions were degassed prior to use.

Reactions under H2 pressure
All reactions under H2 pressure were carried out in glass vials (50 × 14 mm, Schütt), equipped with a magnetic stir bar and a rubber septum in autoclaves BR-100 or Br-300 (including the appropriate heating blocks, Berghof). The autoclave was purged with N2 (3 × 10 bar) before the vials were placed in the autoclave and the septum was pierced under a counter flow of N2.
The autoclave was purged with N2 (1 × 1 bar, 3 × 10 bar) and H2 (3 × 10 bar) or D2 (2 × 5 bar) before the appropriate H2 or D2 pressure was applied (pressure is given as initial pressure before heating). The heating block was pre-heated before the autoclave was placed inside.
After the respective reaction time the autoclave was allowed to cool to rt and H2 or D2 was released. The autoclave was purged with N2 (3 × 10 bar) before the vials were taken out.

Chemicals
All reagents were purchased from established commercial suppliers (Sigma-Aldrich, Alfa Aesar, TCI, Acros, Strem, Merck, ABCR, Fluka, Fisher Scientific) and used without further purification. NaOt-Bu was sublimed and stored in an Ar-filled glovebox. 15-crown-5 was dried over 3 Å MS, distilled under N2 atmosphere and stored under N2 over 3 Å MS. H2 (99.999%) and D2 (99.8%) was purchased from Air Liquide. Methyl 4-(1,3-dioxan-2-yl)benzoate (10) [2] and [3] was synthesized following known procedures. Notes: Before transferring the reaction mixture to the autoclave, it was necessary to have a tight closed reaction vial and to work under inert conditions. NaOt-Bu had to be sublimed and stored in a glovebox. 15-crown-5 had to be dried as described before. Between addition of the substrate and pressurizing with H2 were approximately 5 min.

General procedure 2 -Ball mill synthesis attempts for [CuGua] 5
The synthesis was carried out using the Fritsch Pulverisette 7 classic line, a high-energy planetary ball mill. The starting materials 1-(2-(2,3-diisopropyl-1-methylguanidino)ethyl)-3mesityl-1H-imidazol-3-ium bromide (3, 75 mg, 0.16 mmol, 1.00 equiv), CuCl (16.5 mg, 0.16 mmol, 1.00 equiv) and a base (0.25 mmol, 1.50 equiv) were filled into a 12 mL steel vessel equipped with six steel balls (1 cm diameter). The beaker was sealed in an Ar-filled glovebox. Milling was carried out with 450 rpm for a total of four hours. After each hour the milling was paused for 30 minutes to avoid overheating of the machine. The ground product was mixed with CH2Cl2 (3 mL) and the resulting suspension was filtered over a PTFE syringe filter (0.45 μm). The filtrate was concentrated under reduced pressure.
Notes: For experiments with sodium hydride (NaH) as a base a 45 mL zirconia vessel with six zirconia balls (1.5 cm in diameter) was used.

Synthesis of [Cu(IMes)Cl] (7a)
Synthesis was carried out using the FRITSCH Pulverisette 7 classic line, a high-energy planetary ball mill. Data is in accordance with literature. [4] The amount of the cationic dimer complex was calculated from 1 H-NMR spectra using the integrals of the signals at 7.05 ppm for the desired complex and 7.10 ppm for the cationic dimer complex.

Synthesis of [Cu(SIMes)Cl] (7b)
Synthesis was carried out using the FRITSCH Pulverisette 7 classic line, a high-energy planetary ball mill. The data is in accordance with literature. [4]

Synthesis of [Cu(IPr)Cl] (7c)
Synthesis was carried out using the FRITSCH Pulverisette 7 classic line, Data is in accordance with literature. [5]

Synthesis of [Cu(SIPr)Cl] (7d)
Synthesis was carried out using the FRITSCH Pulverisette 7 classic line, Data is in accordance with literature. [5] The amount of the cationic dimer complex was calculated from 1 H NMR spectra using the integrals of the signals at 7.40 ppm for the desired complex and 7.48 ppm for the cationic dimer complex. The signal at 3.00-3.11 ppm integrates too high because of an overlap of signals for the desired complex and the cationic dimer complex.

Benzyl alcohol (9)
Prepared according to GP1 from ethylbenzoate (8,  The data is in accordance with literature. [6]

Evidence for the formation of 5ꞏCO2
Attempts were carried out to isolate and characterize the suggested CO2 adduct of complex 5.
However, the complex could not be isolated due to limited stability. Nevertheless, the crude 1 H NMR spectrum as follows shows that all key resonances are present. Further evidence comes from the HRMS of the crude mixture as depicted below. Figure S5: Crude 1 H NMR of 5ꞏCO2. S16 Figure S6: Mass spectrum of 5ꞏCO2.
In addition to these data, reactivity studies further support the formation of a CO2 adduct with complex 5, and that this adduct is catalytically inactive: When the standard catalytic hydrogenation of ethyl benzoate was carried out under standard conditions, [9] but CO2 was bubbled through the solution of 5 at rt for 5 minutes prior to the catalytic reaction, no conversion in the catalytic hydrogenation of esters was observed.
This shows that coordination of CO2 to the complex prevents any reactivity in the catalytic ester hydrogenation. This finding is in support of our hypothesis that the guanidine subunit is turned into a hydrogen bond donor upon protonation in situ. Complexation of CO2 prevents the formation of any hydrogen bonds to the ester substrate, resulting in an inactive catalyst.
We have furthermore measured the elemental analysis of the CO2 adduct of 5 after several months of storage in an Ar filled glovebox: